Algorithmic and computational models for probing congenital heart diseases through TLL1 gene and GATA transcription factor

Abstract

Degradomics - the proteomics analysis of proteases - is reforming the understanding of proteases function. By revealing their substrate repertoire, also called the substrate degradome, the crucial biological roles of proteases is becoming discoverable. Thus, an interesting utility of degradomics is the outcome of protein biomarkers whose role can be symbolic like calpain and caspase proteases, injurious like Matrix Metalloproteinases (MMP-2 and MMP-9), or constructive like the Tll1 gene, depending on the corresponding biological process. In this thesis, we elaborate on the role of the Tll1 protease in Congenital Heart Disease (CHD) and the role of calpain and caspase proteases in brain injury and neuronal cell death types. It has been a challenge to identify the protease cleaved fragments with high precision and efficiency. Recently, advanced proteomics techniques have shown a remarkable progress in identifying them experimentally. We present in this thesis a detection method that identifies them accurately and efficiently, with validation against experiments from the literature. The method aims at predicting the consensus sequence occurrences and their variants in a large set of experimentally detected protein sequences, based on state-of-the-art sequence matching and alignment algorithms. After detection, the method generates all the potential cleaved fragments. This space and time efficient algorithm is flexible to handle the different orientations that the protein and consensus sequences can take before cleavage by the protease. Subsequently, this knowledge will feed into the development of a novel web tool for researchers to detect the diverse types of biomarkers online, and that will guide in the diagnosis and treatment of related diseases. Protein-DNA interactions are of fundamental importance in molecular biology, playing roles in functions as diverse as DNA transcription, DNA structure formation, and DNA repair. Protein-DNA association is also important in medicine and understanding protein-DNA bindi